| Background: Cushing's Syndrome is a term used to describe a set of symptoms such as abnormalities of glucose and lipid metabolism,hypertension and osteoporosis associated with hypercortisolism caused by different factors.Cortisol-producing adrenocortical adenomas(ACAs)is the main cause of adrenal Cushing's syndrome.Recent investigations have demonstrated that somatic mutation of PRKACA,resulting aberrant c AMP/PKA signaling pathway,contributed to the development of ACAs.The mutation resulted in persistently acticiating of the PKA pathway,thus stimulating the synthesis of cortisol.Genetic sequencing and molecular classification of ACAs would contribute to clinical diagnosis and prognosis of adrenal Cushing's snydrome.However,lacking of reliable markers restricts the rapid and economic pathological approach in the molecular diagnosis of ACAs.In addition,central obesity is common in Cushing's syndrome patients and associated to altered adipokine secretion,further contributing to insulin resistance,inflammation and fat accumulation.There have been several reports demonstrating an increase in sereum resistin level in Cushing's snydrome.Besides,we have previous reported that the m RNA level of resistin was upregulated in ACAs with PRKACA mutation.However,the specific mechanism involved in resistin regualtion in adrenal is still unclear.Objective:1?The pathological features of ACAs correlating with the driver somatic mutations and molecular classification remains unclear.Here we explore the association between the steroidogenic acute regulatory protein(St AR)expression and the driver mutations activating c AMP/PKA signaling to identify pathological marker in ACAs.2?Becouse of the discovery of increase of resistin expression in ACAs tissues with PRKACA somatic mutation,we want to explore the regulation mechanism of resistin expression in adrenal glands.Design and methods:1?Immunohistochemical staining of St AR and the mutations of PRKACA?PRKAR1A and GNAS were examined in 97 ACAs.The association of St AR expression and clinical and mutational features of ACAs was analyzed.2?We detected the serum resistin levels in ACAs patiensts,and overexpressed wt-or mut-PRKACA in H295 R and SW13 cell lines to explore the regulation mechanism of resistin in adrenal.Furthermore,we explored the relationship of serum ACTH and resistin in ACAs patients and adrenal resistin m RNA levels were analysed in saline or ACTH treated mice to investigate the effects of ACTH on adrenal resistin expression.Results:1?Immunohistochemical analysis showed strong St AR staining in PRKACA,GNAS and PRKAR1 A mutant ACAs.The concordance between high St AR expression and the mutation activating c AMP/PKA signaling in ACAs was 99.0%.ACAs with high St AR expression presented significantly smaller tumour volume(P<0.0001)and higher urinary cortisol per tumour volume(P = 0.035).2?In patients with mutation,the sreum levels of resistin were much higher compared with the wild-type PRKACA,and the mutated one showed a remarked rise in its ability to transactivitate the h-Resistin promoter.In addition,we found a positive correlation between serum ACTH and resistin in ACAs patients.In vivo study showed that ACTH also up-regulated the expression of resistin in mice adrenal glands by activating the PKA pathway.Conclusions:1?Our findings revealed that immunohistochemical staining of St AR is a reliable pathological approach for diagnosis and classification of ACAs with the mutations activating c AMP/PKA signaling.2?Our findings suggested a new role of adrenal glands acting as a source of adipokine,resistin,by activating the PKA pathway,affecting human metabolism despite of canonical cortical and medulla hormones in response to ACTH... |
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